The earlier part of this project focused on myelin basic protein (MBP) structure. Prediction from the known amino acid sequence suggested an organized structure with 25% B-sheet, and challenged the prevailing view of MBP as a disordered protein without long-range intramolecular interactions. This new structure is consistent with an "organizer" role for MBP in myelin, and should lead eventually to an understanding of its structural role. This model is sufficiently detailed to be testable. S.J. Morris in our laboratory has begun fluorescence energy transfer studies which test predictions of the proximity of the naturally fluorescent residues Trp and Tyr. A key feature of MBP is the triproline sequence, the function of which is predicted by the model. The ProProPro sequence follows the sole phosphorylated threonine residue, Thr-99, and appears to be a recognition site for this protein kinase. A search of other known sequences revealed that a similar site occurs in SV40 virus T-antigen, and that the human papova viruses JC and BK have a comparable site with the sequence Pro Lys Thr Pro Pro Pro. The recognition of the common function of these sites in a viral protein and the differentiated product of one of its host cells raises fundamental questions concerning protein evolution, protein kinase identity and specificity, and cross-reactive epitopes. Of primary concern to us are the implications for mechanisms of demyelination. Accordingly, we have examined frozen PML sections for the presence of T-antigen using a sensitive immunocytochemical technique. We detected T-antigen in all 5 cases of PML studied, and found it expressed in many more cells than are virion antigens. We then assessed 9 cases of MS and found no evidence of T-antigen expression. We feel this rules out "enzymological" demyelination in MS in which T-antigen competes for the MBP threonine protein kinase. However, the abundance of T-antigen in infected human PML tissue strengthens the possibility that an immune response to the T-antigen of JC or BK virus plays a role in the etiology of MS.